For synthesis of (4E)-5-chloro-2-isopropyl-4-pentenoates and their analogues, the following processes have been reported.
(1) A process for producing a 5-chloro-2-isopropyl-4-pentenoate by reacting methyl isopentanoate with 1,3-dichloro-1-propene in the presence of lithium diisopropylamide (LDA) at an extremely low temperature (−78° C.) (U.S. Pat. No. 4,492,799).
(2) The process (1) in which the reaction is carried out at −15° C. by using sodium iodide (NaI) for higher reactivity (Examples in WO02/08172 and WO01/09079).
(3) A process for synthesizing 5-chloro-2-isopropyl-4-pentenoic acid, which comprises quaternary alkylation of diethyl isopropylmalonate with 1,3-dichloro-1-propene in ethanol as a solvent in the presence of sodium ethoxide (NaOC2H5), hydrolysis of the two ester linkages and monodecarboxylation of the resulting dicarboxylic acid (“Akad. Nauk Armyan, S. S. R. Khim. Nauki”, 1960, vol. 13 (4), p. 259-262, (Russia)).
(4) A process for synthesizing various 4-pentenoate derivatives, which comprises quaternary alkylation of a diethyl malonate derivative with a chloropropene derivative in toluene as a solvent in the presence of sodium hydride (NaH) and dealkoxycarbonylation of either ester linkage (U.S. Pat. No. 4,492,799).
For synthesis of optically active (S)-(4E)-5-chloro-2-isopropyl-4-pentenoates and their analogues, the following processes have been reported.
(5) A process for producing ethyl (S)-(4E)-5-chloro-2-isopropyl-4-pentenoate, which comprises adding porcine liver esterase (Roche Diagnostics, Technical Grade) all at once to the racemic ethyl (4E)-5-chloro-2-isopropyl-4-pentenoate obtained by the process (2) (WO01/09079).
(6) A process for producing (S)-(4E)-5-chloro-2-isopropyl-4-pentenoic acid, which comprises hydrolyzing the racemic ethyl (4E)-5-chloro-2-isopropyl-4-pentenoate obtained by the process (2), treating the resulting racemic (4E)-5-chloro-2-isopropyl-4-pentenoic acid with optically active cinchonidine for diastereomeric salt formation, separating the (S)-diastereomer salt by recrystallization and treating the (S)-diastereomeric salt with an acid (WO01/09079).
The reports of the processes (1), (3) and (4), however, are silent about the E/Z ratio of the double bond in the 5-chloro-2-isopropyl-4-pentenoates. Further, while the process (2) was reported to give the E-isomers of a 5-chloro-2-isopropyl-4-pentenoate in yields of 84% and 76%, reproduction of experiments disclosed therein by the present inventors did not gave the E-isomer in the reported yield, but in a yield of only about 4.2%. Thus, it has been difficult to selectively synthesize the E-isomer of 5-chloro-2-isopropyl-4-pentenoates in high yields without isomerization to the Z-form.
Further, because the use of lithium diisopropylamide (LDA) requires that the reaction temperature must be kept thermostatically at such an extremely low temperature as −78° C., and because LDA is prepared from expensive n-butyllithium (n-BuLi), the process (1) is unsuitable for industrial mass production for economical reasons and in view of operational difficulties and gives the product in such a low yield as 46%. The process (2) has a problem that the product is obtained in a low yield and is difficult to purify because methyl isopentanoate as the starting material undergoes side reactions such as self-condensation. The process (3) has a problem that esterification of 5-chloro-2-isopropyl-4-pentenoic acid, which is obtainable in a 23% yield, gives a 5-chloro-2-isopropyl-4-pentenoate in a still lower yield. The process (4) is economically and operationally unsuitable for industrial mass production in view of the use of NaH.
The report of the process (5) does not sufficiently disclose the reaction conditions for production of an optically active isomer and keeps it totally unclear how to obtain the desired compound at all. The processes (5) and (6) are unsuitable for industrial mass production because the use of the process (2) for production of the racemate to be resolved lowers the total yield considerably.